Pyridine thiosemicarbazone



United States, Patent assignors to Schenley Industries, Inc., New York,N. Y., a corporation of Delaware No Drawing. Application May 7, 1952, 1Serial No. 286, 636 v 4 Claims. (o 250-2943 This invention relates,generally to novel organic compounds, useful because of theirphysiological activities, and, more particularly, it concerns thethiosemicarbazones of certain heterocyclicaromatic aldehydes.

It is known that certain aromatic aldehyde thiosemicarbazones, such asbenzalthiosemicarbazone and 4- acetylaminobenzalthiosemicarbazone, areuseful therapeutic agents against various pathogens, includingStaphylococcus aureus and Mycobacterium tuberculosis. It is also knownthat the physiological activity of an individual number of this largeclass of compounds is not predictable, either qualitatively orquantitatively, based upon the present state of knowledge of thissubject.

According to this invention it is now found that a group of novelisomeric pyridine aldehyde thiosemicarbazones are possessed ofphysiological activity that makes them exceptionally useful therapeuticagents in the treatment of tuberculosis. These new chemical compoundsare represented by the formula:

It will be noticed that the generalized formula above represents thethree isomeric pyridine aldehyde thiosemicarbazones wherein the aldehydegroup is at the 2-, 3- or 4-positions of the pyridine moiety.

The novel compounds of this invention can be readily prepared byreacting thiosemicarbazide with a selected one of the three isomericpyridine aldehydes. This reaction is conducted in the manner usual forthe preparation of aldehyde thiosemicarbazones and, preferably isperformed in an acetic aqueous medium at an elevated temperature nearthe boiling point of the medium. Each of the three compounds of thisinvention, picolin-aldehyde thiosemicarbazone (pyridine-Z-aldehydethiosemicarbazone), nicotinaldehyde thiosemicarbazone(pyridine-3-aldehyde thiosemicarbazone) and isonicotinaldehydethiosemicarbazone (pyridine-4-aldehyde thiosemicarbazone) is found to bea more effective agent against M. tuberculosis than the referencecompound, 4-acetylaminobenzaldehyde thiosemicarbazone. In addition tobeing useful in combating tubercular infections, the compounds of thisinvention are also useful as pesticides.

This application is a continuation-in-part of applicants co-pendingapplication Serial No. 128,022, filed November 17, 1949, entitledProducts Of The Thiosemicarbazone Series.

In order to facilitate a better understanding of the subject matter ofthis invention and how the compounds of this invention may be prepared,several examples follow, provided by way of illustration merely and notby way of limitation upon the scope of this invention.

Example 1 Approximately equimolecular proportions of picolinaldehyde(Z-formyl-pyridine) and thiosemicarbazide are 2,719,161 Patented Sept.27, 1955' cs i reacted together in boiling dilute acetic acid. Thereaction mixture is boiled under reflux for about one-half hour, then itis cooled and the yellowish colored crystals of picolinaldehydethiosemicarbazone, which separate from the supernatant liquor, areremoved, preferably by filtration, washed with water and dried. Theproduct compound. so obtained, pieolinaldehyde thiosemicarba zone, has amelting point of 209 C. and is represented by the formula Example 2About 10.7 g. of 3-formyl pyridine (nicotinaldehyde) and 9.5 g. ofthiosemicarbazide are boiled for 30 minutes in a solution of cc. ofwater to which has been added 5 cc. glacial acetic acid. Thenicotinaldehyde thiosemicarbazone begins to separate as coarse,pale-yellow crystals even while the solution is still hot. Thesecrystals are removed by filtration and dried. Their melting point isabout 216 C., with decomposition. The product dissolves in dilutehydrochloric acid and in dilute sodium hydroxide solution, yielding ayellow solution, and it forms a copper complex salt which may berecovered as a greenish, yellow powder. This product, nicotinaldehydethiosemicarbazone, is represented by the formula:

Example 3 Approximately 100 g. of isonicotinic acid hydrazide aredissolved in 500 cc. of pyridine and g. of benzene sulfonyl chloride areslowly added to this solution. The mixture is stirred for several hoursat 3040 C. Most of the pyridine is distilled OK in vacuo and the residueis poured into water, whereupon N'-benzenesulfonyl isonicotinic acidhydrazide separates as coarse crystals, which melt at 148 C. after beingrecrystallized from water.

About 27.7 g. of this product are dissolved in 100 cc. ethylene glycolat a temperature of C. and 25 g. of anhydrous potassium carbonate arestirred into the solution within a period of about 3 minutes. Thegaseous products evolved are passed, for washing, into 300 cc. of cooledwater in order to recover any isonicotinaldehyde which may be containedtherein. After the initial almost-violent reaction has taken place, the300 cc. of wash water are poured into the reaction mixture, 10 g. ofthiosemicarbazide are added, and the solution is acidified by additionof acetic acid. The mixture is boiled for 30 minutes, then allowed tocool, and after standing for several hours, the crystalline depositwhich forms is removed by filtration and washed with water. It isdissolved in boiling dilute hydrochloric acid (1%), the solution ispurified with animal charcoal, filtered, and a sodium acetate solutionis then added to the hot filtrate. The product, isonicotinaldehydethiosemicarbazone precipitates as coarse yellow crystals which melt at226-228 C., with decomposition. The product may be recrystallized fromdilute ethanol or water: if it is recrystallized from water, it issometimes obtained as nearly colorless needles that collect in rosetteswhich, when heated decompose at a temperature of 226-228 3 C. Thecompound dissolves in sodium hydroxide solution and in hydrochloric acidto yield a yellow solution,

and'it forms a greenish-yellow copper complex' salt.

The product is represented by the formula:

CH=N.NH.G (:S) .NHz'

2. Thethi'oscmicarbazone of Z-pyridine aldehyde having the followingformula:

3. The thiosemicarbazone of 3-pyridine aldehyde having the followingformula:

4. The thiosemicarbazone of 4-pyridine aldehyde having the followingformula:

No references cited.

1. A COMPOUND REPRESENTED BY THE FORMULA: